It’s not just genetics

THIS WORK IS A TRANSLATE OF THE FOLLOWING POST:Non è solo genetica

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Until not many years ago (but sometimes even nowadays) it was commonly believed that the phenotype (intended as the morphological and functional characteristics) of an organism was influenced solely by the genetic patrimony of the individual: any variation in the phenotype was ascribable to some mutation in the genome of the organism itself. Although this statement is to a good extent correct, the progress of knowledge and molecular techniques has placed us in front of issues that could no longer be explained only with classical genetics. A typical example is that of homozygous twins; they share exactly the same genetic heritage and yet, however they may resemble each other, they will always show some more or less evident differences. But since their genetic heritage is identical, how can we explain a phenomenon of this kind? Should not they be identical?

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Questions like this have led researchers to brush up on concepts that have been theorized by some pioneers over the course of history, but never really accepted and seriously investigated.

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Epigenetics

In recent years, epigenetic became a hot topic in science, and this discipline has succeeded in combining classical genetics, completing it, in many fields, including medicine and evolution. Epigenetics refers to the set of inheritable mechanisms that are able to vary the phenotype of an organism without varying its DNA sequences. Thus, epigenetic mutations, called epimutations, are not able to modify the genetic heritage of organisms, but they can change the way in which it is expressed, giving rise to different phenotypes.
If we think about it, it is quite clear how, actually, epigenetics regulates the development of each one of us in a fairly important way. The cells that make up our body all come from the same cell, the zygote, formed from a maternal and a paternal gamete; the genome of the zygote is formed by the fusion of the two gametes, it has 50% of the maternal genetic material and 50% of the paternal one. But if all the cells are derived from the zygote, how can they perform such different and sometimes incompatible functions with each other? The answer lies precisely in the epigenetic mechanisms that are able to "inactivate" the part of DNA that does not serve that particular cell function, making the useful part more active. By making it trivial, we could take as an example a nerve cell and a muscle cell. The expression of two motor proteins, actin and myosin, is essential in muscle cells; the sequences coding for these products must therefore be particularly "accessible" so that they can be easily transcribed. On the contrary, it would not make sense for these proteins to be produced in abundance in a neuron, where the production of neurotransmitters could be more important. Yet, neuron and muscle cell have exactly the same genetic makeup. The epigenetic regulation, then, will make more room for the genes for myosin and actin in the muscles, and the genes for the neurotransmitters in the neurons.
To this "traditional" vision of epigenetics, recent studies have added a fundamental element: some modifications are inheritable. We have said that all cells derive from the zygote and therefore, if we consider the hypothesis that due to an error or due to an external stimulus epimutations occur at the zygote level, it seems reasonable that these mutations can then find a way to express themselves in the adult organism. In the same way, taking a further step backwards, we have seen how the zygote is formed by the two parental gametes; the idea that epimutations in the parents' gametes may somehow influence the epigenetic expression of the child might then be just as reasonable.

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Molecular mechanism

Despite the complexity of this topic, the molecular mechanisms are basically simple and well known:

• DNA methylation. DNA methylation is a very well known process and consists in the attachment of methyl groups to DNA strands. The methyl groups protect the helix from the attack of different types of enzymes and proteins. The protection mechanism is elementary and basically based on steric encumbrances: if a methyl group is present, the transcription factors will not have the physical space to reach the DNA. High methylation, therefore, corresponds to the silencing of that gene tract.
• Acetylation of histones. Histones are globular proteins around which DNA is normally wrapped. DNA has a slight negative charge, which facilitates the link with the histones, which are instead slightly positive.Acetylation shield the positive charge, decreasing the affinity between histone and DNA. This weaker bond facilitates the interaction with transcription factors. Therefore, greater acetylation corresponds to a greater expression.
• Methylation of histones. Unlike acetylation, histone methylation causes repression of transcription; in fact, it facilitates the binding with a specific protein that further condenses the histone-filament structure, making access for transcription factors complicated. Other forms of histone regulation, less studied, are phosphorylation and ubiquitination.
• Gene silencing. They are produced by RNAi (RNA interference) that interact with the mRNAs (messengers RNA) already produced preventing their translation. Probably the expression of RNAi is due to one of the modifications described above. These mechanisms all contribute to the important function of regulating the expression of the genome, without ever going to modify it. It may seem exaggerated to believe that it is sufficient to modify the quantities of the transcripts to generate so many differences, but in recent years many evolutionists are beginning to believe that these processes play a role of primary importance also in evolution: differences in gene expression could be at the base of the evolution. Just think of the great resemblance between our genome and that of other mammals very different from us. The difference, then, could reside right in the different quantities of transcripts we produce.

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Molecular structures of histones.}

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Disputes

Up to this point the speech is quite linear and, as supported by numerous experimental evidence, irrefutable. The first controversy within the scientific community exploded when geneticists began to consider the possibility that epigenetic modifications could also be induced by the environmental context within which an organism develops. If two homozygous twins are perfectly identical on a genetic level, net of possible random mutations of their DNA, what else can cause a diversification of the phenotypes? Most probably it is the environment they live in, understood as the multiplicity of different situations that everyone has to face in their lives. Emotions, fears, traumas that each one faces in the course of one's life are able to modify our epigenetic code and to transmit it, at least in part, in a hereditary way. After all, it is not a new concept that a trauma can mark the existence of a person; today we can say that, probably, at a molecular level this mechanism is driven precisely by epigenetics. Trying again to trivialize, repeated situations of great fear could lead to a continuous expression of genes that "code for fear"; the body, then, makes this package of genes that are used often more accessible. This, however, results in more efficient transcription even in the presence of minor stimuli and, in the long run, can generate a sensation of frequent fear that could in turn cause states of anxiety. If these epigenetic modifications are therefore hereditary, this means that somatic modifications induced by the environment are, at least in part, transmissible by inheritance.

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Methylation of a cytosine.}

This possibility is against most modern theories that says that no somatic modification is able to cross the Weismann barrier, an ideal barrier, which prevents somatic mutations from "turning back" and transmitting to the germline ,spreading themselves . Despite initial opposing views, contemporary studies are constantly demonstrating and confirming this thesis.

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Experimental evidences

Two important researches have been conducted to try to better understand the epigenetic mechanisms. The first one, performed in the laboratory, investigated the use of mice subjected to particularly stressful conditions with the aim of observing and investigating the effects on the offspring. The second one, constituted more than anything else by an imposing data collection, aimed to consider what are the effects of the winter of hunger were on the children of people who had experienced it in the first person.

In the first experiment, were used mice which, during pregnancy, was given a diet with half caloric intake compared to normal. As expected, mothers have produced smaller but healthy children. However the interesting aspect of the research was the observation of the evolution of the health conditions of these second-generation individuals (F2); in fact, they have shown a greater predisposition to the development of obesity and diabetic state when they reach adulthood. Another aspect of interest was the detection of similar problems, albeit in an attenuated form, in the third-generation (F3) individuals, the grandchildren of the mothers exposed to the treatment. At this point, taking for granted the transmission of the epigenetic code by the mother, the researchers investigated whether there were any differences from the normal condition in the spermatozoa of F2 mice and actually there was a lower degree of methylation in some areas of the DNA.

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The second experiment is has to be considered a completely natural test, as it is not influenced by laboratory conditions. The "winter of hunger" corresponds to the cold winter of 1944, at the end of the Second World War, when the Reich's troops blocked all supplies to the occupied areas of the Netherlands. It is estimated that, during this period, the daily diet of civilians corresponded to a caloric intake not exceeding 500 calories per capita. Obviously during that winter there were still numerous pregnant women and the study tried to retrieve data related to these mothers to investigate the effects on the following generations. As observed in mice, the children of those who had experienced famine showed an increased incidence of cardiovascular disease, diabetes and obesity in adulthood. There are currently no data available on the F3 generation, the grandchildren of those mothers, as these people are reaching today the age group of interest, but data collection goes on and you will have more precise ideas in a short time.

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Molecular mechanism related to insulin resistance, type II diabetes.}

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Conclusions

The researchers' hypothesis is that, during a situation of food scarcity, in the mother occur epigenetic modifications that render the transcription of genes involved in nutrients assimilation more efficient. In this context, in fact, it is essential to get the maximum from food. These changes are then inherited by their children, who may find themselves no longer living with a poor diet such as that of their parents. At this point the organism would now be predisposed to assimilate as many calories as possible; but this, in a "normal" diet can easily result in the appearance of obesity or other diseases related to nutrients metabolism. If we wanted to make a concrete hypothesis, we could venture that the increase in cases of metabolic diseases and obesity that we see in recent years is linked to some phenomenon of this type. The ability to assimilate most of what we eat could be a legacy left to us by our grandparents who, in many cases, have experienced the rigidity of war. Today, however, we live in a world where food does not represent (at least in the West) a limiting factor and is often abused. Our epigenetic code, however, has not yet had time to "update" to the new situation and requires us to metabolize everything as during a famine.

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The F3 model

If this model proves correct, we should look at a similar situation in the F3 generation. Beyond the F3 generation, everything is still very uncertain. The human model (more generally that of mammals) theorize that during the formation of the zygote a complete decondensation of DNA occurs, and this should in a sense "reset" the epigenetic code. This implies that the germ line of the F3 generation has a completely new epigenetic code and therefore, the F4 is healthy and completely different from the previous ones. In mice this hypothesis seems confirmed, now we just have to wait until the current human F4 (children of today) reach adulthood to get some reliable data. As a partial support of this thesis, it was observed that similar experiments conducted in the C. Elegans nematode, without the reset-code mechanism, led to the transmission of the epigenetic code even up to generation F50.

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Future

The hope is that, in the future, we can use these discoveries to treat diseases that today impact very negatively on life and its quality. Epigenetic mechanisms, in fact, are at the base of the development of some forms of cancer: an excessive methylation of the factors that control and prevent the development of cancer, for example, could facilitate its onset. The exact understanding of these mechanisms, which by their nature are changeable, could help the development of new and effective therapies.

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References

• Robin Holliday (2006). Epigenetics: A Historical Overview.
  https://doi.org/10.4161/epi.1.2.2762
• Gerda Egger, Gangning Liang, Ana Aparicio & Peter A. Jones (2004). Epigenetics in human disease and prospects for epigenetic therapy.
  https://www.nature.com/articles/nature02625
• Scott F. Gilbert, D. Epel (2009). ** Ecological Developmental Biology: Integrating Epigenetics, Medicine, And Evolution**.
  http://works.swarthmore.edu/fac-biology/141/
• Shelley L. Berger, Tony Kouzarides, Ramin Shiekhattar and Ali Shilatifard (2009). An operational definition of epigenetics.
  https://doi.org/10.1101/gad.1787609
• Elizabeth A. Mazzio & Karam F.A. Soliman (2011). Basic concepts of epigenetics: impact of environmental signals on gene expression.
  https://doi.org/10.4161/epi.7.2.18764
• Leslie A. Pray (2004 – in progress). Epigenetics: Genome, meet your environment: as the evidence for epigenetics, researchers reacquire a taste for Lamarckism.

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